Neonatal presentations of mitochondrial metabolic disorders

Neonatal Presentations of Mitochondrial Metabolic Disorders Carolyn M. Sue, Michio Hirano, Salvatore DiMauro, and Darryl C. De Vivo

Because of the high energy requirements of the growing neonate, disorders of mitochondrial metabolism caused by defects in fatty acid oxidation, pyruvate metabolism, and the respiratory chain may often present in the neonatal period. Common neonatal presentations are hypotonia, lethargy, feeding and respiratory difficulties, failure to thrive, psychomotor delay, seizures, and vomiting. Laboratory clues include alterations in the levels of lactate, pyruvate (and the lactate/pyruvate ratio), glucose, and ketone bodies. Diagnosis usually depends on specific enzyme assays or on molecular genetic analysis. Without treatment, most infants die in the first few days or months of life. In the last decade, there have been significant advances in the understanding of the molecular basis of these disorders. This review discusses the major subgroups of mitochondrial disorders, focusing on defects of pyruvate oxidation, the Krebs cycle, and the respiratory chain. Disorders caused by respiratory chain defects may involve nuclear DNA, mitochondrial DNA, or intergenomic signaling. Recognition and early diagnosis of these conditions are important in the genetic counseling of these families.

Copyright 9 1999 by W.B. Saunders Company iseases related to the m i t o c h o n d r i o n have been reported in the literature for a little m o r e than 35 years. 1 During this time, a growing n u m b e r of disorders has been attributed to defects in the mitochondrial metabolic pathways. Although originally reported as the "mitochondrial myopathies," the clinical spectrum of these disorders has e x p a n d e d to include multiple organ systems, in a variety of combinations, which may present at virtually any age. Mitochondria are essential cell organelles found in all nucleated mammalian cells. T h e i r principal function is to p r o d u c e the bulk of the energy required for normal cellular function. Mitochondria generate energy in the form of adenosine triphosphate (ATP) via oxidative phosphorylation. This process produces ATP by harnessing the energy released from the oxidation of fatty acids and sugars via the electron transport chain (Fig 1). Those tissues that are more d e p e n d e n t on aerobic metabolism, such as

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From the Departments of Neurology and Pediatrics, H. Houston Merritt Clinical Research Centerfor Muscular Dystrophy and Related Diseases, Columbia University College of Physicians and Surgeons, New York, NY. Address reprint requests to Darryl C. De Vivo, MD, Sidney Carter Professor of Neurology and Professor of Pediatrics, Neurological Institute, 710 West 168th St, New York, NY 10032. Copyright 9 1999 by W.B. Saunders Company O146-0005/99/2302-0003510. 00/0

brain, muscle, and heart, are more likely to be affected in these disorders. Similarly, the rapidly increasing energy requirements o f the growing neonate r e n d e r it vulnerable to defective energy metabolism; this accounts for the frequent neonatal presentation of mitochondrial disorders. Interestingly, mitochondria contain their own genetic material, which is distinct from that conrained in the nucleus (nuclear DNA or nDNA). Mitochondrial DNA (mtDNA) is 16, 569 base pairs long and encodes 13 respiratory chain proteins as well as two ribosomal proteins and the tRNAs that are required to assemble these proteins. Thus, mitochondrial function is u n d e r dual genetic control from nuclear and mitochondrial DNA. Mutations within both the nDNA and mtDNA have been associated with mitochondrial disorders. This r e p o r t concentrates on the neonatal presentations o f disorders in which mitochondrial metabolism is disturbed. T h e neonatal period, for the purpose of this review, has been defined as the first 6 months of life. A classification of disorders of mitochondrial metabolism is outlined in Table 1. These disorders fall into three main subgroups: defects of fatty acid oxidation, defects of pyruvate metabolism, and defects of the respiratory chain, all o f which can p r o d u c e severe brain dysfunction in the neonatal period. In general,

Seminars in Perinatology, Vol 23, No 2 (April), 1999: pp 113-124

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Figure 1. Schematic representation of the mitochondrial metabolic pathways: neonatal presentations include clinical features such as hypotonia, lethargy, feeding and respiratory difficulties, failure to thrive, psychomotor delay, seizures, and vomiting. Without treatment, most infants die in the first few days or months of life. Neonatal presentations of defects of fatty acid metabolism will be addressed in other sections of this journal 2,3 and will not be discussed here. A flowchart for the diagnosis of disorders of mitochondrial metabolism is outlined in Fig 2.

Disorders of Pyruvate Metabolism Pyruvate Dehydrogenase Complex Deficiency Pyruvate d e h y d r o g e n a s e complex (PDHC) is a multienzyme complex that catalyzes the con-

version of pyruvate to acetyl coenzyme A (CoA). It is located in the mitochondrial matrix a n d is composed of three catalytic components; E 1 (pyruvate dehydrogenase), E 2 (dihydrolipoyl transacetylase), a n d E 3 (dihydrolipoyl dehydrogenase) and of two regulating enzymes (PDH kinase and PDH phosphatase). The regulating enzymes either activate (by dephosphorylation) or inactivate (by phosphorylation) the first c o m p o n e n t (El), a process that is d e p e n d e n t on ATP. The E 1 enzyme c o m p o n e n t is a m a d e u p of two oz a n d two /3 subunits that are linked together as a tetramer. Although genetic defects in each of the five enzyme c o m p o n e n t s have been associated with disease conditions, the most c o m m o n subunit affected is Ea~, e n c o d e d by a gene on the X c h r o m o s o m e (Xp22.1). The Eat3 subunit is en-

Mitochondrial Disorders in the Neonate

Table 1. Classification of Disorders of

Mitochondrial Metabolism Nuclear DNA defects Defects of substrate transport CPT deficiency* Carnitine deficiency* Defects of substrate utilization Pyruvate dehydrogenase complex deficiency* Pyruvate carboxylase deficiency* Defects of/3-oxidation* Defects of the Krebs cycle Dihydrolipoyl dehydrogenase deficiency* a-ketoglutarate dehydrogenase deficiency* Fumarase deficiency* Defects of oxidative phosphorylation Luft's disease Defects of respiratory chain Complex I deficiency* Complex II deficiency* Complex III deficiency* Complex IV deficiency* Complex V deficiency Defects of translocases Adenine nucleotide transiocator deficiency Carnitine-acylcarnitine deficiency* Porin deficiency* Defects of protein importation Methylmalonic acidemia Heat shock protein deficiency* Defects of intergenomic signaling Multiple mtDNA deletions MtDNA depletion syndrome* Mitochondrial DNA defects Large scale rearrangements* Point mutations affecting structural genes* Point mutations affecting ribosomal RNAs* Point mutations affecting tRNAs* Abbreviation: CPT, carnitine palmitoyltransferase * Subgroup in which neonatal presentations have been reported. coded by a gene on c h r o m o s o m e 3 and is m u c h less frequently affected. PDHC deficiency, an autosomal or X-linked recessive condition, is a major cause of primary lactic acidosis in infants and young children. 4 The clinical course may be quite variable, and there is a predominance of severely affected boys, consistent with the fact that most genetic abnormalities in this disorder involve the X c h r o m o s o m e - e n c o d e d Ex~, subunit. Characteristically, patients present with metabolic acidosis and neurological dysfunction. Because of its obligatory requirement for aerobic glucose oxidation, the adverse consequences of PDHC deficiency are greatest in the brain. Hence, this condition is distinguished by the presence of

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anatomic abnormalities in the central nervous system. Commonly, patients with PDHC deficiency present with Leigh syndrome (LS), 5,6 a clinical syndrome that is characterized by a subacute necrotizing encephalopathy associated with bilateral symmetrical lesions in the putamen and brainstem. In the most severe form of PDHC deficiency, lactic acidosis develops within hours of birth. This is often associated with an altered level of consciousness, profound hypotonia, lethargy, feeding and respiratory difficulties, and coma. There may be periods of episodic apnea. Birth weight is often low. Seizures may occur in one third of patients, and one quarter suffer from dysmorphic facial features such as a broad nasal bridge, upturned nose, micrognathia, low set and posteriorly rotated ears, as well as simian creases, hypospadia, or an anteriorly placed anus. The lactic acidosis is usually refractory to therapy, and most of these patients die in the newborn period. In the more benign forms of this disease, patients may survive for periods up to months or years. These children may display developmental delay, lethargy, hydrocephalus, seizures, episodic apnea, optic atrophy, ptosis, dysphagia, other cranial nerve palsies, hypotonia, weakness, pyramidal tract signs, peripheral neuropathy, ataxia, and dysmorphic facial features. Arterial and cerebral spinal fluid (CSF) lactate levels usually are elevated. However, as the oxidation-reduction potential is maintained, the lactate/pyruvate ratio usually is normal. Neuroimaging shows absence or partial absence of the corpus callosum, cavitating lesions in the cerebral white matter, symmetrical putaminal and brainstem lesions, and diffuse cerebral atrophy. Patients who die in the neonatal period often have generalized cerebral edema or multiple hemorrhages. In the other forms of PDHC deficiency, there may be focal structural abnormalities characterized by cystic lesions with areas of spongiform change in the white matter, basal ganglia, and brainstem. Diagnosis of PDHC deficiency is confirmed by measuring PDH activity in cultured fibroblasts or by identifying the DNA defect. Those children who die early usually have a low residual enzyme activity, although correlation between the phenotype and genotype is complex and may be influenced by the lyonization effect in girls. For example, a mildly affected mother had

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Figure 2. Flowchart for the diagnosis of disorders of mitochondria metabolism. L, lactate; P, pyruvate; KB, ketone bodies; BSL, blood sugar level; PDH, pyruvate dehydrogenase; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; LCHAD, long-chain acyl-CoA deficiency; SCAD, short-chain acyl-CoA deficiency; CPT, carnifine palmitoyltransferase; HMGCoA, 3-Hydroxy-3-methylglutaryl-CoA lyase. two sons (by different fathers), who both died in the neonatal period. All had the same genetic defect and similar levels of enzyme activity in cultured skin fibroblasts, but both children expressed a more severe form of the disease. 7 More benign forms (especially in girls) may have n o r m a l enzyme activities and molecular analysis using polymerase chain reaction-single strand c o n f o r m a t i o n polymorphism (PCRSSCP), and DNA sequencing may be required to confirm the diagnosis. 8 To date, all biochemically c o n f i r m e d cases have a primary genetic defect involving the EI~ subunit whose gene is located in the short arm of the X chromosome. PDHC deficiency rarely may be caused by other enzyme abnormalities such as lipoamide dehydrogenase deficiency, dihydrolipoyl transacetylase (E2) deficiency, and PDH phosphatase deficiency. Lactic acidemia caused by lipoamide dehydrogenase deficiency is not present at birth and usually becomes apparent during early infancy, whereas the clinical presentations of E 2 deficiency and PDH phosphatase deficiency may occur between the neonatal period and late infancy. E s (dihydrolipoyl dehydrogenase) mutations are associated with severe lactic acidosis, hypotonia, microcephaly and failure to thrive.

Pyruvate Carboxylase Deficiency Pyruvate carboxylase is the main regulating enzyme for gluconeogenesis. Its deficiency is transmitted as an autosomal recessive trait. There are three main clinical phenotypes: two severe forms, Group A (North American phenotype) and Group B (French phenotype) and Group C, the benign phenotype. Clinical presentations of the severe forms include profound hypotonia, psychomotor delay, failure to thrive, and seizures. Group B is more severe than Group A, and patients may die in early infancy. Diagnosis involves the demonstration of elevated serum levels of lactate, ketone bodies (/3hydroxybutyrate and acetoacetate) and ammonia. Hypercitrullemia and hyperlysinemia also are present. The diagnosis is confirmed by measurement of the enzyme activity in skin fibroblasts. Because there is no effective treatment for this disorder, prenatal diagnosis is important and has been successfully performed by measurement of enzyme activity in cultured amniocytes.9

Disorders of the Krebs Cycle Because the Krebs cycle is a crucial pathway in intermediary metabolism, complete defects in-

Mitochondrial Disorders in the Neonate

volving enzymes in this area usually are incompatible with life. 1~ Partial defects are rare. They are characterized by metabolic acidosis with increased lactate-pyruvate ratio and normal or reduced ketone body ratios. Three enzyme defects have been described to date: dihydrolipoyl dehydrogenase deficiency, a-ketoglutarate dehydrogenase deficiency, and fumarase deficiency.

Dihydrolipoyl Dehydrogenase Deficiency Dihydrolipoyl dehydrogenase deficiency was the first enzyme defect of the Krebs cycle to be reported. Although the precise genetic abnormality has not been identified, it is probably an autosomal recessive condition because all parents of affected children have been consanguineous. Infants usually present with severe persistent lactic acidosis during the neonatal period. 11 Other associated clinical features include respiratory difficulties, seizures, dystonic movements, hypoglycemia, lethargy, hypotonia, vomiting, constipation, failure to thrive, and feeding difficulties. 12.13Most patients die in early infancy, but patients who survive to childhood have been reported, ll,x-s Treatment with lipoic acid produced clinical improvement in one case. is

a-Ketoglutarate Dehydrogenase Deficiency ~-Ketoglutarate dehydrogenase deficiency is a rare enzyme deficiency first reported in 1982.14 Although most children with this condition are normal at birth, x4,15 a few patients have had a more severe form with neonatal hypotonia, recurrent attacks of metabolic acidosis and seizures. 16 a-Ketoglutarate dehydrogenase deficiency has been associated with choreoathetosis, opisthotonos, spasticity, hypertrophic cardiomyopathy, hepatomegaly, and sudden death. Diagnosis is confirmed by high levels of glutamate and elevated urinary ketoglutamic acid levels.

Fumarase Deficiency Fumarase deficiency was first described in 198617 and is an autosomal recessive disorder that results from decreased activity of fumarate hydratase. Patients may present in utero with polyhydramnios, TM but the neonatal presentation usually involves severe neurological impairment with seizures or infantile spasms, lethargy, microcephaly, hypotonia, axial dystonia or opisthotonos, areflexia, or psychomotor retardation.

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Other clinical features include acute respiratory distress, leucopenia, and neutropenia. One patient had facial dysmorphism and hepatopathy. 19 Although some children may follow a subacute or chronic course of progressive encephalomyopathy with dementia, hypotonia and dysarthria, 18,2~most patients die within the first year of life. Diagnosis is made by the detection of marked elevation of urinary fumaric acid, often associated with milder elevations of succinic and citric acid. Serum and urinary lactate levels may be mildly elevated during acute metabolic decompensations, but are usually normal during quiescent periods. Cerebral computed tomography (CT) scan may show diffuse cerebral atrophy, and, on one occasion, agenesis of the corpus callosum was reported. 19 Confirmation of this disorder is by enzyme assay of both cytosolic and mitochondrial fumarase activities (both enzymes are encoded by the same gene) in cultured skin fibroblasts or affected tissues. The reduction in enzyme activity does not correlate to the severity of the clinical course. Routine genetic screening for fumarase gene abnormalities on chromosome 1 is of limited clinical value because several different mutations, including missense mutations, 21 deletions, and insertions have been reported. ~2.~3 Neuropathological findings of autopsy cases include microcephaly, hypomyelination, and areas of heterotopia in the cerebellum, occipital, and parietal regions. 24

Disorders of the Respiratory Chain The respiratory chain consists of four enzyme complexes that interact to transfer protons across the mitochondrial membrane, thus creating an electrochemical gradient. A fifth complex (ATP synthetase) uses this energy to convert adenosine diphosphate (ADP) and inorganic phosphate to ATP. As previously mentioned, the respiratory chain is u n d e r the genetic control of both nuclear and mitochondrial DNA.

Nuclear DNA Defects of the Respiratory Chain Neonatal presentations caused by nuclear DNA defects of the respiratory chain have been reported in patients with isolated Complex I, III, or IV deficiencies or multiple enzyme defects.

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These disorders may be sporadic, but often show patterns of Mendelian inheritance. The clinical features of defects in the respiratory chain are variable; they may affect multiple systems and present at any age.

Complex I Deficiency Complex I (NADH-ubiquinone reductase) is the largest respiratory chain enzyme and is responsible for transferring electrons from NADH across the mitochondrial membrane. T h e r e are three reported clinical subgroups of Complex I deficiency: a fatal infantile form, a childhood or adult-onset myopathy characterized by exercise intolerance or weakness, and a childhood-onset encephalomyopathy characterised by ophthalmoplegia, seizures, dementia, and ataxia. T h e fatal infantile form is a multisystemic disorder and usually presents in the first few days of life with severe lactic acidosis, diffuse hypotonia, weakness, hypertrophic cardiomyopathy, hepatomegaly, apneic episodes, feeding difficulties, and cardiorespiratory insufficiency leading to death in the neonatal period, 25-27 Hypoglycemia also has b e e n reported. Death occurs in the first weeks of life. Both familial 27 and sporadic cases 25 have b e e n reported. Muscle biopsy findings may demonstrate ragged-red fibers with the modified Gomori trichrome stain indicating proliferation of mitochondria. Diagnosis is confirmed by the meas u r e m e n t o f enzyme activity in affected organs 25,27 or cultured skin fibroblasts, 26 although, no correlation between residual enzyme .activity and clinical severity has b e e n established. 2s Complex I deficiency may occur as a single enzyme defect or in combination with other respiratory chain defects. 2s,29 Patients with combined enzyme deficiencies tend to have a more severe illness when c o m p a r e d with those patients with isolated Complex I deficiency.2S O n l y one nuclear gene defect in a child with fatal Complex I deficiency has been identified to date. s~ Combined enzyme defects raise the possibility of mtDNA rather than nDNA defects.

Complex III Deficiency Complex III translocates protons across the inner mitochondrial m e m b r a n e and transfers electrons between ubiquinol and cytochrome c. Complex III deficiency has b e e n reported in one

n e o n a t e who had severe lactic acidosis associated with hypotonia, irritability, and muscle wasting. Dystonic posturing, seizures, coma, and lactic acidosis developed in the patient before he died o n day 3. 31 Histological examination of the muscle specimen finding was normal, but biochemical analysis of multiple tissues demonstrated a reduction of Cytochrome b and Complex III activity. A fatal form of cardiomyopathy, histiocytoid cardiomyopathy, also has b e e n r e p o r t e d to be associated with Complex III deficiency. 32 O t h e r less severe forms may present as encephalomyopathy or myopathy ~3 in childhood or adult life.

Complex IV Deficiency Complex IV or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c, the reduction of oxygen and the translocation of protons. COX deficiency usually causes an encephalopathy or a myopathy. The most c o m m o n presentation of COX deficiency is the encephalopathy, which usually presents as LS. s4-36 However, children with COX deficiency and LS are usually asymptomatic until early infancy when they develop psychomotor regression. Myopathic presentations include three main variants: a fatal infantile myopathy, a benign reversible infantile myopathy, and a late-onset (adult) myopathy. Neonatal myopathic presentations of COX deficiency are characterized by generalized hypotonia, weakness, respiratory insufficiency, and lactic acidosis, which may be present from birth. Associated cardiomyopathy 3v and Fanconi's syndrome3S also have been reported. Children with the fatal form of the disorder die from respiratory insufficiency within months. T h e presentation of children with the benign form is identical with the exception that they improve spontaneously if supported aggressively for the first few months of life. Lactic acidosis recedes, and these children b e c o m e clinically normal by early childhood. 39-41More rarely, fatal hepatopathy associated with COX deficiency may occur, either in isolation 42,43 or in combination with an encephalopathy. 44,45 In myopathic patients, muscle biopsies specimens show COX-negative and ragged-red fibers. These abnormalities gradually disappear parallelling clinical i m p r o v e m e n t in children with the benign reversible form of COX deficiency. His-

Mitochonddal Disorders in the Neonate

tochemical staining for COX is absent, and distinguishing between the benign and fatal forms only can be accomplished by immunocytochemistry; lack of reactivity with antibodies against subunit II is present in the benign form, but lack of reactivity with antibodies against subunit VIIab is present in both forms. 46

Disorders Caused by Defects of Translocases Translocases are involved in the transport of metabolites across the inner mitochondrial membrane. Only a few defects in translocases have been associated with h u m a n mitochondrial disorders, and neonatal presentations in this group of defects are rare. Defects in the carnitine-acylcarnitine translocase have been associated with cardiomyopathy, and the first pathogenic mutation in the cDNA for this translocase has been reported in an infant with cardiomyopathy. 47 A decrease in porin, a transporter in the outer mitochondrial membrane, has been reported in a child with dysmorphic features, hypotonia, developmental delay, seizures, and hydrocephalus, 4s but the pathogenicity of this abnormality is unclear because mitochondrial enzyme activities and muscle histochemistry were normal.

Disorders Caused by Defects of Mitochondrial Protein Importation The mitochondrion only synthesises 13 of the polypeptides required for its function. All other mitochondrial proteins are imported into the organelle from the cytoplasm. This requires a complex process involving targeting signals ("leader peptides" located at the N-terminus of most imported proteins), binding to receptors, transfering across inner and outer membrane channels, and unfolding or refolding of proteins by heat shock proteins or "chaperonins. "49 Defects in this multistep process are thought to be lethal if they involve the "general importation" machinery. 5~ However, defective synthesis of heat shock protein 60 (hsp60) has been reported in two patients: a neonate who had multiple mitochondrial enzyme defects and died after 2 days5~ and a child who presented at birth with hypotonia, dysmorphic facial features, and failure to thrive who survived until 4.5 years. 52

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Intergenomic Signaling Defects In this group of disorders, the primary defect is in nuclear DNA, but the consequences are either qualitative or quantitative defects in mtDNA. Qualitative intergenomic signaling defects give rise to multiple mtDNA deletions, which are characterized clinically by progressive external ophthalmoplegia presenting in adults. Quantitative defects, that is, mtDNA depletion syndrome, often present in the neonatal period. Mitochondrial depletion is an autosomal recessive condition that results in a reduction of total mtDNA. It was first described by Moraes in 1991. 53 There are two recognized phenotypes: congenital and infantile onset. The congenital mtDNA depletion syndrome presents with limb weakness, marked hypotonia, and, sometimes, nephropathy or with fatal hepatopathy. Associated seizures and ophthalmoplegia also have been reported. Affected patients usually die in the first year of life. In the infantile onset form, progressive muscle weakness begins around 12 to 14 months of age and may be associated with neuropathy. Some patients have survived until the age of 9 to 10 years. 54,5~ Patients with the congenital form have more severe mtDNA depletion than those with the later onset form. The two forms also can be distinguished histologically; muscle biopsy specimens in the congenital form have little or no immunoreactive mtDNA, and all fibers are COX deficient, whereas biopsy specimens in the less severe infantile form have a "mosaic" pattern, in which some fibers are normal and others lack both mtDNA and COX activity.~5 Molecular diagnosis of this condition requires Southern blot analysis. The cause of mtDNA depletion is unknown, although a deficiency in the h u m a n mitochondrial transcription factor (h-mtTFA) has been postulated. 56

Mitochondrial DNA Defects of the Respiratory C h a i n Because all mitochondria passed onto the progeny are derived from the cytoplasm of the ovum, all disorders associated with mtDNA point mutations show a maternal rather than a Mendelian pattern of inheritance. Conversely, deletions usually occur sporadically. The maternal pattern of inheritance may not necessarily be clinically apparent, because other factors, such as hetero-

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plasmy and threshold effects, play a role in the clinical expression of these disorders. Heteroplasmy refers to the coexistence of m u t a n t and wild-type DNA within the cell. The degree of heteroplasmy varies between different tissues and individual cells within each tissue, and there is some evidence to suggest that heteroplasmy also may occur at an intramitochondrial level. 57-59 Pathogenic mtDNA mutations usually are heteroplasmic. The "threshold effect" refers to the m i n i m u m a m o u n t of a mtDNA mutation, which will lead to impairment of mitochondrial function. Once the threshold is exceeded, mitochondrial dysfunction becomes clinically apparent. 6~ The threshold effect is relative because it is determined not only by the metabolic requirements of the tissue itself, but also by the metabolic d e m a n d at any given time. Thus, susceptibility is not necessarily constant, because energy requirements in tissues may vary with time and during different functional demands. 61 Defects in mtDNA include two major subgroups: largescale rearrangements and point mutations.

Large-Scale Rearrangements of mtDNA Large-scale rearrangements of mtDNA include single deletions, duplications, or both. Usually, only a single type of deletion with or without the corresponding duplication occurs in any one patient. Single deletions usually occur sporadically, but those conditions associated with duplications may be maternally transmitted. 62 Although large-scale rearrangements are most commonly found in patients with Kearns-Sayre syndrome or chronic progressive external ophthalmoplegia, t h e most c o m m o n neonatal presentation associated with mtDNA rearrangements is Pearson's syndrome. Pearson's syndrome is characterized b y refl~actory sideroblastic anemia and exocrine pancreatic dysfunction. 63 There often is an associated pancytopenia. It usually presents in infants and is often fatal. If the patient survives, there is full recovery of the marrow and pancreatic function. Histologically, there is vacuolization of erythroid and myeloid precursors, hemosiderosis, and ringed sideroblasts. Family history is usually unremarkable. There have been three reported patients with Pearson's syndrome who have survived, in whom Kearns-Sayre syndrome developed subsequently. 64-66 Furthermore, an infant

who had hematologic features of Pearson's syndrome and a 3.6 kilobase (kb) mtDNA deletion, later had a rapidly progressive encephalomyopathy that was suggestive of LS. 67 Other neonatal presentations of rearrangements are rare, but one report has described a heteroplasmic duplication of a 4.2-kb deletion in a girl who presented with failure to thrive, anorexia, vomiting, and diarrhea with evidence of severe Complex III deficiency on biochemical analysis of muscle tissue. 6s

Maternally Transmitted Point Mutations MtDNA point mutations have been r e p o r t e d in structural protein, ribosomal RNAs, and tRNAs. The three most c o m m o n clinical presentations associated with point mutations in s t r u c t u r a l genes include Leigh's disease, NARP syndrome (neuropathy, ataxia, a n d retiral pigmentation), and Leber's hereditary optic neuropathy. O t h e r rarer presentations associated with structural gene point mutations include MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), and myopathy with exercise intolerance, weakness, or myoglobinuria. Point mutations reported in ribosomal RNAs present with aminoglycoside-induced hearing loss, whereas those associated with the tRNA genes include MELAS and MERRF syndromes (myoclonus, epilepsy, ragged red fibers) a n d a m u l t i t u d e of overlap syndromes. 1~ A l t h o u g h m a n y patients characteristically have normal early development and, therefore, do n o t present in the neonatal period, occasional early-onset cases do occur and, thus, extend the clinical spectrums of these conditions. Neonatal presentations of mtDNA point mutations are described below. Maternally transmitted point mutations in structural genes. Although the T8993G point mutation located in the ATPase 6 gene was first associated with NARP syndrome, 7~ it has since been recognized to be associated with LS, 71-75 particularly when the mutation is present in high abundance. 73 This disorder, which may present with psychomotor retardation, feeding and respiratory difficulties, cranial nerve palsies, and ataxia, is characteristically associated with neuroradiological evidence of bilateral striatal and brainstem lesions. Leigh's disease is genetically heter-

Mitochondrial Disorders in the Neonate

ogeneous 6 and can be associated with both defects in the nuclear genome and in the mitochondrial genome. However, if there is a positive family history of LS or NARP (ie, maternally inherited LS or maternally inherited Leigh syndrome), or if retinitis pigmentosa is present, the likelihood of finding a mtDNA defect is high. 75 Several other mtDNA heteroplasmic point mutations in the ATPase 6 gene have been associated with Leigh's disease, including T8993C 75,76 and T9176C. 77 Maternally transmitted point mutations in ribosomal

RNAs. Only one mutation, A1555G in the ribosomal RNA 16S subunit, has been described. 78 This is associated with antibiotic-induced hearing loss, although some family members had congenital hearing loss in the absence of other systemic disease/s Maternally transmitted point mutations in tRNAs. More that 50 pathogenic point mutations in mtDNA have been described to date. 69 The most c o m m o n clinical syndromes include MELAS and MERRF syndromes. MELAS syndrome is characterized by recurrent neurological deficits and is usually, although not invariably, associated with the A3243G, T3271C, or T3291C point mutations in the tRNA l.... gene. MERRF syndrome usually is associated with point mutations at A8344G or T8356C in the tRNA TM gene. Although early development characteristically is normal in these conditions, young-onset presentations have been described. 79 Other point mutations that have presented in the neonatal period are listed as follows: (1) The C4320T mutation has been described in a 7-month-old girl with hypotonia, generalized seizures, spastic tetraparesis, and hyporeflexia who died of infantile hepertrophic cardiomyopathy. s~ (2) The T3303C mutation was reported in two siblings in whom cardiac failure and lactic acidosis developed in the first few months of life. There was a family history of myopathy and cardiomyopathy, and sudden cardiac death, st (3) The A3243G mutation has been reported in three children who presented with various combinations of hypotonia, weakness, hyperreflexia, ataxia, atypical retinal pigmentary changes, and seizures in the neonatal period; all of these subsequenfly had severe psychomotor delay in early infancy. 79 (4) The A10044G mutation has been found in a family who had gastroesophageal reflux, asthma, sinusitis, and attention deficit dis-

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order. One sibling died in the neonatal period of sudden unexpected death. 82 (5) The A15923G mutation has been described in a baby 1 girl who died 2~ days after birth after hypoglycemia, lactic acidosis, and sudden multisystem failure developed. 8~ Other mtDNA Abnormalities.

A maternally inherited single thymidine insertion at nt 5537 in the tryptophan tRNAS has been reported in a 10-month-old infant who presented with developmental regression, swallowing difficulties, and blindness, s4 He developed lactic acidosis and died of a sudden cardiorespiratory arrest at the age of 17 months. His siblings also suffered from lactic acidosis and impaired visual acuity. Final C o m m e n t s Clinical presentations of severe, early-onset mitochondrial disease should alert the neonatologist to investigate family members of the proband to identify other patients who may have mitochondrial disease. Furthermore, neonates who present with mitochondrial disorders should call attention to the possibility that neurological or multisystemic problems in (maternal) relatives may be caused by mitochondrial disorders. References 1. Luft R, lkkos D, Palmieri G: A case of severe hypermetabolism of non thyroid origin with a defect in the maintenance of mitochondrial respiratory control; a correlative clinical, biochemical, and morphological study. J Clin Invest 41:1776-1804, 1962 2. Strauss AW, Bennett M, Rinaldo P, et al: Acute fatty liver of pregnancy, HELLP syndrome, and neonatal LCHAD deficiency. Semin Perinatol 23:100-112, 1999 3. Scaglia F, Longo N: Primary and secondary alterations of neonatal carnitine metabolism. Semin Perinatol 23:152161, 1999 4. Brown G, Brown R, Scholem R, et al: The clinical and biochemical spectrum of human pyruvate dehydrogenase complex deficiency. Ann NY Acad Sci 573:360-368, 1989 5. DeVivo D, Haymond M, Obert K, et al: Defective activation of the pyruvate dehydrogenase complex i subacute necrotizing encephalomyelopathy (Leigh disease). Ann Neurol 6:483-494, 1979 6. DiMauro S, De Vivo DC: Genetic heterogeneity in Leigh syndrome. Ann Neurol 40:5-7, 1996 7. Fujii T, Van Coster R, Old S, et al: Pyruvate dehydroge-

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